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Definitions

• the present invention relates to a carbamoyl-substituted spiro derivative.
• histamine which is a biologically active endogenous factor functions as a neurotransmitter and has a pharmacological activity within a broad range (refer, for example, to Life Science, vol. 17, page 503 (1975 )).
• histaminergic nerve in nodular papillary nucleus of posterior hypothalamus suggests that, in brain function, histamine plays an important role in the control of physiological functions particularly related to the functions of hypothalamus (such as sleeping, awaking rhythm, incretion, behavior of taking food and water and sex behavior) (refer, for example, to Progress in Neurobiology, volume 63, page 637 (2001 )).
• histaminergic nerve fiber is projected to the region related to maintenance of wakefulness (such as cerebral cortex) suggests the role played by histamine in adjusting the wakefulness or a cycle of awakening and sleeping.
• histaminergic nerve fiber is projected to many marginal structures such as hippocampus and amygdaloid complex suggests the role of histamine in the adjustment of autonomic nerve, in the control of emotion and motivated behavior and in the learning and memorizing process.
• histamine When histamine is released from producing cells, it plays its pharmacological actions as a result of action to specific polymer called a receptor on a cell membrane surface or in a target cell and conducts the adjustment of various physical functions.
• a receptor on a cell membrane surface or in a target cell
• histamine H3 receptor the presence of histamine H3 receptor has been shown by various pharmacological and physiological studies (refer, for example, to Trends in Pharmacological Science, volume 8, page 24 (1986 )).
• human and rodential histamine H3 receptor gene has been identified and its presence has been clarified (refer, for example, to Molecular Pharmacology, volume 55, page 1101 (1999 )).
• Histamine H3 receptor is present in presynaptic membrane of central or peripheral nerve cells functioning as a self-receptor and controls not only release of histamine but also release of other neurotransmitters.
• histamine H3 receptor agonist, antagonist or inverse agonist regulates the liberation of histamine, noradrenaline, serotonin, acetylcholine, dopamine, etc. from nerve terminal.
• a histamine H3 receptor agonist such as (R)-( ⁇ )-methylhistamine and is promoted by a histamine H3 receptor antagonist such as thioperamide or inverse agonist (refer, for example, to Trends in Pharmacological Science, volume 19, page 177 (1998 )).
• an object of the present invention is to provide a novel substance having an antagonistic action against a histamine H3 receptor (an action which inhibits the bonding of histamine to histamine H3 receptor) or an inverse agonistic action (an action which suppresses a homeostatic activity of histamine H3 receptor) or, in other words, to provide a novel substance acting as a histamine H3 receptor agonist or antagonist in living body.
• the present inventors have found that specific carbamoyl-substituted spiro derivatives act as a histamine H3 receptor antagonist or inverse agonist and achieved the present invention.
• the present invention provides the compounds or salts thereof mentioned in the following (1) to (17) in order to achieve the above-mentioned object.
• the compound or salt mentioned in the above (1) to (16) acts in a living body as a histamine H3 receptor antagonist or inverse agonist.
• the present invention also provides a histamine H3 receptor antagonist or inverse agonist comprising the compound or a pharmaceutically acceptable salt thereof mentioned in any of the above (1) to (17).
• a histamine H3 receptor has a very high homeostatic activity (activity observed in the absence of an endogenous ergogenic factor (such as histamine)) in receptor-expressing cells/tissues or membrane fractions derived therefrom or in living body (refer, for example, to Nature, volume 408, page 860 ) and the homeostatic activity as such has been reported to be suppressed by an inverse agonist.
• an inverse agonist for example, thioperamide or ciproxifan suppresses the homeostatic self-receptor activity of the histamine H3 receptor and, as a result, it promotes the release of neurotransmitters (such as histamine) from nerve terminal.
• thioperamide which is a histamine H3 receptor antagonist or inverse agonist increases the awakening state in a dose-dependent manner and thioperamide decreases slow wave and REM sleep (refer, for example, to Life Science, volume 48, pages 2397 (1991 )).
• Thioperamide or GT-2331 which is a histamine H3 receptor antagonist or inverse agonist also decreases affective cataplexy and sleep of narcolepsy dogs (refer, for example, to Brain Research, volume 793, page 279 (1998 )).
• H3 receptors may participate in control of vigilance sleep and in sleep disorder-associated disease, further suggesting a possibility that selective histamine H3 agonists, antagonists or inverse agonists may be useful for prevention or treatment of sleep disorder and various diseases accompanied by sleep disorder (such as idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic limb movement disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, sleep unwholesomeness of night-work laborers, idiopathic insomnia, repetitive insomnia, true insomnia, depression, anxiety and schizophrenia). Accordingly, the compounds mentioned in the above (1) to (16) and salts thereof acting as histamine H3 receptor antagonists or inverse agonists are believed to be effective for prevention or treatment of sleep disorder and various diseases accompanied thereby.
• sleep disorder such as idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic limb
• thioperamide or GT-2331 which are a histamine H3 receptor antagonist or inverse agonist improves the symptoms of learning disability (LD) and attention-deficient/hyperactivity disorder (ADHD) (refer, for example, to Life Science, volume 69, page 469 (2001 )).
• ADHD attention-deficient/hyperactivity disorder
• rats (R)-( ⁇ )-methylhistamine which is a histamine H3 receptor agonist lowers a recognizing ability to objective and learning effect in a recognizing test for objective and a passive withdrawal test.
• thioperamide which is a histamine H3 receptor antagonist or inverse agonist reduces the amnesia on a dose-dependent manner (refer, for example, to Pharmacology, Biochemistry and Behavior, volume 68, page 735 (2001 )).
• histamine H3 receptor antagonists or inverse agonists are useful for prevention or treatment of memory and learning disability and various diseases accompanied by that (such as Alzheimer's disease, Parkinson's disease and attention deficit/hyperactivity disorder). Accordingly, the compounds or salts thereof mentioned in the above (1) to (16) are also believed to be effective for prevention or treatment of memory and learning disability and various diseases accompanied by that.
• thioperamide which is a histamine H3 receptor antagonist or inverse agonist suppresses the eating behavior on a dose-depending manner while it promotes the liberation of histamine in brain (refer, for example, to Behavioral Brain Research, volume 104, page 147 (1999 )).
• histamine H3 receptors participate in control of eating behavior and histamine H3 antagonists or inverse agonists are useful for prevention or treatment of metabolic diseases such as eating disorder, obesity, diabetes, emaciation and hyperlipemia. Accordingly, the compounds or salts thereof mentioned in the above (1) to (16) are also believed to be effective for prevention or treatment of metabolic diseases as such.
• (R)-( ⁇ )-methylhistamine which is a histamine H3 receptor agonist lowers a basal diastolic blood pressure on a dose-depending manner.
• Such an action is antagonized by thioperamide which is a histamine H3 receptor antagonist or inverse agonist (refer, for example, to European Journal of Pharmacology, volume 234, page 129 (1993 )).
• histamine H3 receptors participate in control of blood pressure, heart beat and cardiovascular output and that histamine H3 receptor agonists, antagonists or inverse agonists are useful for prevention and treatment of circulatory diseases such as hypertension and various cardiac diseases. Accordingly, the compounds or salts thereof mentioned in the above (1) to (16) are also believed to be effective for prevention or treatment of the circulatory diseases as such.
• thioperamide which is a histamine H3 receptor antagonist or inverse agonist has been shown to suppress spasm which is induced by electric stimulation or epilepsy-like attack induced by pentylenetetrazole (PTZ) on a dose-depending manner (refer, for example, to European Journal of Pharmacology, volume 234, page 129 (1993 ) and Pharmacology, Biochemistry and Behavior, volume 68, page 735 (2001 )).
• histamine H3 receptor antagonists or inverse agonists are useful for prevention and treatment of epilepsy or central convulsion. Accordingly, the compounds or salts thereof mentioned in the above (1) to (16) are also believed to be effective for prevention or treatment of epilepsy and central convulsion as such.
• the present invention also provides a preventive or treating agent for metabolic diseases, circulatory diseases or neural diseases which contains a compound mentioned in any of the above (1) to (16) or a pharmaceutically acceptable salt thereof as an effective ingredient.
• At least one which is selected from the group consisting of obesity, diabetes, dysendocrinism, hyperlipemia, gout and fatty liver may be exemplified.
• At least one which is selected from the group consisting of stenocardia, acute congestive cardiac insufficiency, myocardial infarction, coronary sclerosis, hypertension, renal disease and electrolyte imbalance may be exemplified.
• At least one which is selected from the group consisting of sleep disorder, disease accompanied by sleep disorder, hyperphagia, emotional disturbance, epilepsy, delirium, dementia, attention deficit/hyperactivity disorder, memory disorder, Alzheimer's disease, Parkinson's disease, recognition disorder, motion disorder, paresthesia, dysosmia, resistance to morphine, narcotic dependence, alcoholic dependence and tremor may be exemplified.
• At least one which is selected from the group consisting of idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic limb movement disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, sleep unwholesomeness of night-work laborers, idiopathic insomnia, repetitive insomnia, true insomnia, depression, anxiety and schizophrenia may be also exemplified.
• the compounds and the salts thereof mentioned in the above (1) to (16) may also be used together with a co-drug.
• the present invention further provides a preventive or treating agent for metabolic diseases, circulatory diseases or neural diseases containing the compound mentioned in the above (1) to (16) or a pharmaceutically acceptable salt thereof and a co-drug as effective ingredients.
• the co-drug are a treating agent for diabetes, a treating agent for hyperlipemia, a treating agent for hypertension and an anti-obesity agent. Two or more of each of the co-drugs as such may be used jointly.
• a preventive or treating agent for metabolic diseases, circulatory diseases or neural diseases containing the following (i), (ii) and (iii) may be further provided.
• aryl group are a hydrocarbon-ring aryl group having 6 to 14 carbons such as phenyl group, naphthyl group, biphenyl group and anthryl group.
• Heteroaryl group means a five- or six-membered monocyclic group having 1 to 4 hetero atom(s) selected from the group consisting of oxygen atom, sulfur atom and nitrogen atom in the heteroaryl group or means a bicyclic heteroaryl group in which the above monocyclic heteroaryl group is fused with a benzene ring or a pyridine ring and its examples are furyl group, thienyl group, pyrrolyl group, imidazolyl group, triazolyl group, thiazolyl group, thiadiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazolyl group, pyrazinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinolidinyl group, quinoxalin
• “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon(s) and its examples are methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-eth
• Alkoxy group is a group in which hydrogen atom of hydroxyl group is substituted with the aforementioned lower alkyl group and its examples are methoxy group, ethoxy group and propoxy group.
• Cycloalkyl group is preferably a cycloalkyl group having 3 to 9 carbons and its examples are cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and cyclononyl group.
• Alkyl group means the aforementioned lower alkyl group having the aforementioned aryl group and its examples are benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-naphthylmethyl group and 2-naphthylmethyl group.
• Heteroarylalkyl group means a group in which the aforementioned heteroaryl group and the aforementioned alkyl group are bonded and its examples are furan-3-ylmethyl group, furan-2-ylmethyl group, furan-3-ylethyl group, furan-2-ylethyl group, furan-3-ylpropyl group, furan-2-ylpropyl group, thiophen-3-ylmethyl group, thiophen-2-ylmethyl group, thiophen-3-ylethyl group, thiophen-2-ylethyl group, thiophen-3-ylpropyl group, thiophen-2-ylpropyl group, 1H-pyrrol-3-ylmethyl group, 1H-pyrrol-2-ylmethyl group, 1H-pyrrol-3-ylethyl group, 1H-pyrrol-2-ylethyl group, 1H-pyrrol-3-ylpropyl group, 1H-pyrrol-2-ylpropyl group
• Halogen atom means, for example, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
• X, Y, Z and W each independently represent a methine group which may have substituent(s) selected from the group consisting of a substituent group ⁇ .
• Metal group which may have substituent(s) selected from the group consisting of a substituent group ⁇ is an unsubstituted methine group or a methine group having a substituent at the position where substitution is possible and the substituent can select one or more being same or different or, preferably, one from the group consisting of a substituent group ⁇ .
• the substituent group ⁇ comprises a halogen atom, a hydroxyl group, a lower alkyl group (the group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group), a cycloalkyl group (the group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group), an alkoxy group (the group may be substituted with a halogen atom or a hydroxyl group), a cycloalkoxy group (one of carbon atoms constituting the cycloalkoxy group may be substituted with a nitrogen atom, and the nitrogen atom may be substituted with an alkanoyl group), an amino group, a cyano group, a mono- or di-lower alkylamino group, a formyl group, an alkanoyl group, a mono- or di-lower alkylcarbamoyl group, an arylcarbamoyl group,
• substituent group ⁇ more preferred one is a halogen atom, a hydroxyl group, a lower alkyl group (the group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group), a cycloalkyl group (the group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group), an alkoxy group, a cycloalkoxy group (one of carbon atoms constituting the cycloalkoxy group may be substituted with a nitrogen atom and the nitrogen atom may be substituted with an alkanoyl group), cyano group, an alkanoyl group, a lower alkylsulfonyl group, a lower alkylthio group, an aryl group, an aryloxy group or a heteroaryl group and more preferred one is a halogen atom, a hydroxyl group, a lower alkyl group (the group may be substituted with a halogen
• halogen atom which is the substituent
• examples thereof are fluorine atom, chlorine atom, bromine atom and iodine atom.
• examples thereof are methyl group, ethyl group, n-propyl group and isopropyl group.
• the lower alkyl group may be substituted with a halogen atom, a hydroxyl group or an alkoxy group.
• Examples of the lower alkyl group substituted with halogen atom are fluoromethyl group, chloromethyl group, 2-fluoroethyl group and 2-chloroethyl group.
• Examples of the lower alkyl group substituted with hydroxyl group are hydroxymethyl group and 2-hydroxyethyl group.
• Examples of the cycloalkyl group of the substituent are cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group.
• the cycloalkyl group may be substituted with halogen atom, hydroxyl group or an alkoxy group.
• alkoxy group of the substituent examples include methoxy group, ethoxy group and isopropoxy group.
• the alkoxy group may be substituted with halogen atom or hydroxyl group.
• the cycloalkyloxy group of the substituent means a group where the aforementioned cycloalkyl group and oxygen atom are bonded and, to be more specific, its examples are cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group and cyclohexyloxy group.
• One of carbon atoms constituting the cycloalkyloxy group may be substituted with a nitrogen atom.
• the cycloalkyloxy group in which one carbon atom is substituted with a nitrogen atom is preferably a 4- to 7-membered aliphatic ring, concretely including, for example, an azetidin-3-yloxy group, a pyrrolidin-3-yloxy group, a piperidin-4-yloxy group, a homopiperidin-4-yl group et al.
• the nitrogen atom in the three- to seven-membered nitrogen-containing aliphatic ring as such may be substituted with an alkanoyl group, a lower alkylsulfonyl group, diphenylmethyl group, formyl group or a lower alkoxycarbonyl group.
• Examples of the lower alkanoyl group are acetyl group and propionyl group.
• the lower alkylsulfonyl group means a group where the afore-defined lower alkyl group and sulfonyl group are bonded and, to be more specific, its examples are methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, propylsulfonyl group and butylsulfonyl group.
• the lower alkoxycarbonyl group means a group where the lower alkoxy group and carbonyl group are bonded and, to be more specific, its examples are methoxycarbonyl group, ethoxycarbonyl group and isopropyloxycarbonyl group.
• the mono-(lower alkyl)amino group of the substituent means amino group which is mono-substituted with the aforementioned lower alkyl group and its examples are methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, sec-butylamino group and tert-butylamino group.
• the di-(lower alkyl)amino group of the substituent means an amino group is di-substituted with the same or different afore-mentioned lower alkyl groups and its examples are dimethylamino group, diethylamino group, dipropylamino group, methylpropylamino group and diisopropylamine group.
• the alkanoyl group of the substituent means a group where the aforementioned alkyl group and carbonyl group are bonded and its examples are methylcarbonyl group, ethylcarbonyl group, propylcarbonyl group and isopropylcarbonyl group.
• the mono-(lower alkyl)carbamoyl group of the substituent means a group where carbamoyl group which is mono-substituted with the aforementioned lower alkyl group and its examples are methylcarbamoyl group, ethylcarbamoyl group, propylcarbamoyl group, isopropylcarbamoyl group, butylcarbamoyl group, sec-butylcarbamoyl group and tert-butylcarbamoyl group.
• the di-(lower alkyl)carbamoyl group of the substituent means a carbamoyl group which is di-substituted with the same or different aforementioned lower alkyl groups and examples of the "di-lower alkylcarbamoyl group" are dimethylcarbamoyl group, diethylcarbamoyl group, ethylmethylcarbamoyl group, dipropylcarbamoyl group, methylpropylcarbamoyl group and diisopropylcarbamoyl group.
• the arylcarbamoyl group of the substituent means a group where one or two aforementioned "aryl group(s)" and carbamoyl group are bonded and its examples are phenylcarbamoyl group, naphthalen-1-ylcarbamoyl group and naphthalen-2-ylcarbamoyl group.
• the heteroarylcarbamoyl group of the substituent means a group where one or two "the aforementioned heteroaryl group(s)" and carbamoyl group are bonded and its examples are furan-2-ylcarbamoyl group, furan-3-ylcarbamoyl group, thiopen-2-ylcarbamoyl group, thiophen-3-ylcarbamoyl group, 1H-pyrrol-2-ylcarbamoyl group, 1H-pyrrol-3-ylcarbamoyl group, 1H-imidazol-2-ylcarbamoyl group, 1H-imidazol-4-ylcarbamoyl group, 3H-imidazol-4-ylcarbamoyl group, 4H-[1,3,4]triazol-3-ylcarbamoyl group, 2H-[1,2,4]triazol-3-ylcarbamoyl group, 1H-[1,2,4]
• the arylalkylcarbamoyl group of the substituent means a group where one or two of the aforementioned "aralkyl group(s)" and carbamoyl group are bonded and its examples are benzylcarbamoyl group, 1-phenylethylcarbamoyl group, 2-phenylethylcarbamoyl group, 1-naphthylmethylcarbamoyl group and 2-naphthylmethylcarbamoyl group.
• the heretoarylalkylcarbamoyl group of the substituent means a group where one or two of the aforementioned "heteroarylalkyl group(s)" and carbamoyl group are bonded and its examples are furan-3-ylmethylcarbamoyl group, furan-2-ylmethylcarbamoyl group, furan-3-ylethylcarbamoyl group, furan-2-ylethylcarbamoyl group, furan-3-ylpropylcarbamoyl group, furan-2-ylpropylcarbamoyl group, thiophen-3-ylmethylcarbamoyl group, thiophen-2-ylmethylcarbamoyl group, thiophen-3-ylethylcarbamoyl group, thiophen-2-ylethylcarbamoyl group, thiophen-3-ylpropylcarbamoyl group, thiophen-2
• the lower alkylsulfonyl group of the substituent means a group where the aforementioned lower alkyl group and sulfonyl group are bonded and its examples are methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group and butylsulfonyl group.
• the lower alkylthio group of the substituent means a group where the aforementioned lower alkyl group and sulfur atom are bonded and its examples are methylthio group, ethylthio group, propylthio group and isopropylthio group.
• the aryloxy group of the substituent means a group where the aforementioned aryl group and oxygen atom are bonded and its examples are phenoxy group, naphthalen-1-yloxy group and naphthalen-2-yloxy group.
• the aryloxycarbonylamino group of the substituent means a group where the aforementioned aryloxy group and carbonylamino group are bonded and its examples are phenoxycarbonylamino group, etc.
• arylalkyloxycarbonylamino group of the substituent examples include benzyloxycarbonylamino group, 1-phenylethyloxycarbonylamino group, 2-phenylethyloxycarbonylamino group, 1-naphthylmethyloxycarbonylamino group and 2-naphthylmethyloxycarbonylamino group.
• the alkoxycarbonylamino group of the substituent means a group where the aforementioned alkoxy group and carbonylamino group are bonded and its examples are methoxycarbonylamino group, ethoxycarbonylamino group and propoxycarbonylamino group.
• the alkanoylamino group of the substituent means a group where the aforementioned alkanoyl group and amino group are bonded and its examples are methylcarbonylamino group, ethylcarbonyl amino group, propylcarbonylamino group, isopropylcarbonylamino group and isobutylcarbonylamino group.
• the arylcarbonylamino group of the substituent means a group where the aforementioned aryl group and carbonylamino group are bonded and its examples are phenylcarbonylamino group, naphthalen-1-ylcarbonylamino group and naphthalen-2-ylcarbonylamino group.
• the arylalkylcarbonyl group of the substituent means a group where the aforementioned aralkyl group and carbonyl group are bonded and its examples are benzylcarbonyl group, naphthalen-1-ylcarbonyl group and naphthalen-2-ylcarbonyl group.
• the lower alkylsulfonylamino group of the substituent means a group where the aforementioned lower alkyl group and sulfonylamino group are bonded and its examples are methylsulfonylamino group, ethylsulfonylamino group, isopropylsulfonylamino group and n-butylsulfonylamino group.
• the arylsulfonylamino group of the substituent means a group where the aforementioned aryl group and sulfonylamino group are bonded and its examples are phenylsulfonylamino group, naphthalen-1-ylsulfonylamino group and naphthalen-2-ylsulfonylamino group.
• the lower alkylsulfamoyl group of the substituent means a group where one or two of the aforementioned "alkylamino group(s)" and sulfonyl group are bonded and its examples are methylsulfamoyl group, ethylsulfamoyl group, propylsulfamoyl group, isopropylsulfamoyl group, dimethylsulfamoyl group, diethylsulfamoyl group, ethylmethylsulfamoyl group and isopropylmethylsulfamoyl group.
• the arylsulfamoyl group of the substituent means a group where the aforementioned aryl group and aminosulfonyl group are bonded and its examples are phenylsulfamoyl group, naphthalen-1-ylsulfamoyl group and naphthalen-2-ylsulfamoyl group.
• heteroaryl group of the substituent the same group as the aforementioned heteroaryl group may be listed.
• A represents -(C(R 3 )(R 4 )) m1- , -C(O)-, -O- or N(R 5 )-.
• R 3 and R 4 each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group.
• R 5 represent a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group.
• -C(R 3 )(R 4 )- represented by A
• its specific examples are a single bond, a methylene group, -CH(CH 3 )- and -C(CH 3 ) 2 , etc. and, among them, a single bond, a methylene group, etc. are preferred.
• -N(R 5 )- represented by A its examples are -NH-, a methylamino group, an ethylamino group and an isopropylamino group, etc. and, among them, -NH-, a methylamino group, an ethylamino group, etc. are preferred.
• B represents -N(SO 2 R 1 )-, -N(COR 2 )-, -N(R 50 )-, -O- or -C(O)-.
• R 1 and R 2 each independently represent a hydrogen atom, a lower alkyl group, an aralkyl group or an aryl group.
• R 50 represents a hydrogen atom or a lower alkyl group.
• Examples of -N(SO 2 R 1 )- represented by B are a methanesulfonylamino group, an ethanesulfonylamino group, an isopropylsulfonylamino group, a benzylsulfonylamino group and a phenylsulfonylamino group, etc. and, among them, a methanesulfonylamino group, an ethanesulfonylamino group, etc. are preferred.
• Examples of -N(COR 2 )- represented by B are a methylcarbonylamino group, an ethylcarbonylamino group, an isopropylcarbonylamino group, a phenylcarbonylamino group and a benzylcarbonylamino group, etc. and, among them, a methylcarbonylamino group, an ethylcarbonylamino group, etc. are preferred.
• Examples of -N(R 50 )- represented by B are -NH-, a methylamino group, an ethylamino group, an isopropylamino group, a benzylsulfonylamino group and a phenylsulfonylamino group, etc. and, among them, -NH-, a methylamino group and an ethylamino group are preferred.
• D represents -(C(R 30 )(R 40 )) m2 -, -O-, -N(R 51 )- or -C(O)-.
• R 30 and R 40 each independently represent a hydrogen atom, a hydroxyl group, a lower alkyl group, an aralkyl group or an aryl group.
• R 51 represents a hydrogen atom or a lower alkyl group.
• Examples of -(C(R 30 )(R 40 )) m2 - represented by D are a single bond, a methylene group, -CH(CH 3 )- and -C(CH 3 ) 2 -, etc..
• Examples of -N(R 51 )- represented by D are -NH-, a methylamino group, an ethylamino group and an isopropylamino group and, among them, -NH-, a methylamino group and an ethylamino group are preferred.
• Q represents a methine group or a nitrogen atom.
• the group represented by the above formula (III-1) the group represented by the formula (III-1-1), (III-1 -2), (III-I-3), (III-I-4), (III-I-5), (III-I-6), (III-I-7) or (III-I-8), (III-I-9) is preferred and the group represented by (III-1-3), (III-1-4), (III-1-5), (III-1-6) or (III-1-7) is more preferred.
• R represents a group of the following formula (II) [wherein, the symbols have the same meanings as above].
• R 6 represents a hydrogen atom or a lower alkyl group.
• R 7 and R 8 each independently represent a lower alkyl group, a cycloalkyl group, an aralkyl group, a heteroarylalkyl group or R 7 and R 8 together with nitrogen atom to which they bond form a four- to eight-membered nitrogen-containing aliphatic heterocyclic group.
• the group represented by (II-1), (II-2), (II-3) or (II-4) is preferred and the group represented by (II-1) is more preferred.
• the compound represented by the formula (I-1) [wherein, the symbols have the same meanings as above] covered by the formula (I) can be produced by, for example, the following process. [wherein, Hal represents a halogen atom, L 1 represents a methanesulfonyl group, a trifluoromethanesulfonyl group or a p-toluenesulfonyl group, etc. and other symbols have the same meanings as above.]
• This step is a process for producing a compound (2) by the reaction of the compound (1) with 1,4-cyclohexanedione monoethyleneketal in the presence of a base.
• Examples of the compound (1) used in the present reaction are 2-bromo-6-methoxybenzoic acid, 2-bromo-5-methoxybenzoic acid, 2-bromo-4-methoxybenzoic acid, 2-bromo-3-methoxybenzoic acid, 2-bromo-6-fluoroethyloxybenzoic acid, 2-bromo-5-fluoroethyloxybenzoic acid, 2-bromo-4-fluoroethyloxybenzoic acid, 2-bromo-3-fluoroethyloxybenzoic acid, 2-bromo-6-fluorobenzoic acid, 2-bromo-5-fluorobenzoic acid, 2-bromo-4-fluorobenzoic acid, 2-bromo-3-fluorobenzoic acid, 2-bromo-6-methylbenzoic acid, 2-bromo-5-methylbenzoic acid, 2-bromo-4-methylbenzoic acid, 2-bromo-3-methylbenzoic acid, 2,5-dibromobenzoic
• Amount of the 1,4-cyclohexanedione monoethyleneketal used in this step to one equivalent of the compound (1) is usually 1 to 5 equivalent(s) and, preferably, 1 to 2 equivalent(s).
• Examples of a base used are butyl lithium and lithium 2,2,6,6-tetramethylpiperidide.
• Amount of the base used to one equivalent of the compound (1) is usually 2 to 10 equivalents and, preferably, 2 to 4 equivalents.
• reaction solvent there is no particular limitation so far as it does not affect the reaction and examples thereof are tetrahydrofuran (THF), diethyl ether and tert-butyl methyl ether, etc. in which THF is preferred.
• Reaction temperature is usually from -100°C to 100°C and, preferably, from -78°C to 50°C.
• Reaction time is usually from 1 hour to 48 hours and, preferably, from 1 hour to 24 hours.
• the compound (2) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process where a ketal group of the compound (2) produced in the above step 1 is removed to produce a compound (3). Removal of the ketal group can be carried out by a method mentioned in a document (such as " Protective Groups in Organic Synthesis” by T. W. Green, second edition, John Wiley & Sons, 1991 ), by a method similar thereto or by combining those methods with a conventional method.
• hydrochloric acid sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, etc. may be used in the removal of the acetal group.
• Amount of hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid, etc. used to 1 equivalent of the compound (1) is usually from 0.1 to 100 equivalent(s) or, preferably, from 0.5 to 50 equivalent(s).
• reaction solvent in this step there is no particular limitation so far as it does not affect the reaction and its examples are water and water-containing methanol, ethanol, acetone, THF, 1,4-dioxane and acetic acid where methanol, ethanol, acetone, THF and 1,4-dioxane are preferred.
• Reaction temperature is usually from 0°C to 200°C and, preferably, from 20°C to 150°C.
• Reaction time is usually from 1 hour to 48 hours and, preferably, from 1 hour to 10 hours.
• the compound (3) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (4) by subjecting the carbonyl group of the compound (3) produced in the above-mentioned step (2) to a reducing reaction.
• Examples of the reducing agent used in this step are sodium borohydride, lithium borohydride, lithium aluminum hydride and diisobutyl aluminum hydride, etc.
• Amount of the reducing agent used in this step to 1 equivalent of the compound (3) is usually from 1 to 20 equivalent(s) and, preferably, form 1 to 3 equivalent(s).
• reaction solvent there is no particular limitation for the reaction solvent so far as it does not affect the reaction and its examples are THF, a mixed solvent of THF with water, 1,4-dioxane, a mixed solvent of dioxane with water, methanol, ethanol, diethyl ether and dichloromethane, etc. where THF and a mixed solvent of THF with water are preferred.
• Reaction temperature is usually from -100°C to 100°C and, preferably, from -100°C to 50°C.
• Reaction time is usually from 5 minutes to 24 hours and, preferably, from 5 minutes to 4 hours.
• the compound (4) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing the compound (5) by the reaction of the compound (4) produced in the above-mentioned step 3 with a compound L 1 -Cl in the presence of a base.
• the base used in this step are triethylamine, sodium carbonate, potassium carbonate, diisopropylethylamine and pyridine, etc. where triethylamine and diisopropylethylamine are preferred.
• Amount of the base used to one equivalent of the compound (4) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• Examples of the compound L 1 -Cl used in this step are methanesulfonyl chloride, trifluoromethanesulfonyl chloride, p-toluenesulfonyl chloride and benzenesulfonium chloride, etc. where methanesulfonyl chloride and p-toluenesulfonyl chloride are preferred.
• Amount of the L 1 -Cl used to one equivalent of the compound (4) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• reaction solvent there is no particular limitation for the reaction solvent so far as it does not affect the reaction and its examples are THF, methylene chloride, chloroform and ethyl acetate, etc. where THF, methylene chloride and chloroform are preferred.
• Reaction temperature is usually from 0°C to 100°C and, preferably, from 0°C to 50°C.
• Reaction time is usually from 5 minutes to 12 hours and, preferably, from 5 minutes to 4 hours.
• the compound (5) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (6) by the reaction of the compound (5) produced in the above-mentioned step 4 with a CN compound.
• CN compound used in this step are tetraethylammonium cyanide, tetrabutylammonium cyanide, sodium cyanide and potassium cyanide, etc. where tetraethylammonium cyanide and tetrabutylammonium cyanide are preferred.
• Amount of the cyano compound to one equivalent of the compound (5) is usually from 1 to 20 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• reaction solvent there is no particular limitation for the reaction solvent so far as it does not affect the reaction and its examples are N,N-dimethylformamide, THF, dimethyl sulfoxide and acetonitrile, etc. where N,N-dimethylformamide is preferred.
• Reaction temperature is usually from 0°C to 150°C and, preferably, from 50°C to 100°C.
• Reaction time is usually from 1 hour to 48 hours and, preferably, from 1 hour to 24 hours.
• the compound (6) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process to produce a compound (7) by hydrolysis of the compound (6) produced in the above-mentioned step 5 in the presence of an acid.
• Examples of the acid used are sulfuric acid and hydrochloric acid, etc.
• Amount of the acid used to one equivalent of the compound (6) is usually from 1 to 100 equivalent(s) and, preferably, from 1 to 50 equivalent(s).
• reaction solvent there is no particular limitation for the reaction solvent so far as it does not affect the reaction and its examples are dioxane and water, etc.
• Reaction temperature is usually from 20°C to 200°C and, preferably, from 50°C to 150°C.
• Reaction time is usually from 1 hour to 72 hours and, preferably, from 1 hour to 24 hours.
• the compound (7) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (I-1) of the present invention by the reaction of the compound (7) produced in the above-mentioned step 6 with a compound (IV-1), (IV-2), (IV-3), (IV-4) or (IV-5).
• an amide-forming reagent as such are thionyl chloride, oxalyl chloride, N,N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N,N'-carbonyldiimidazole, diphenylphosphoryl chloride, diphenylphosphoryl azide, N,N'-disuccinimidyl carbonate, N,N'-disuccinimidyl oxalate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-chloro-1,3-dimethylimidazolinium chloride, ethyl chloroformate, isobutyl chloroformate, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter, referred to as "HATU”) and benzo
• Examples of the base used are a tertiary aliphatic amine such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-azabicyclo[4.3.0]non-5-ene (DBN), etc.; an aromatic amine such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline; etc.
• the tertiary aliphatic amine is preferred and, for example, triethylamine or N,N-diisopropylamine is particularly preferred.
• condensing promoter examples include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboxyimide and 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, etc. where N-hydroxybenzotriazole, etc. are preferred.
• Amount of the compound (IV-1), (IV-2), (IV-3), (IV-4) or (IV-5) to one equivalent of the carboxylic acid derivative (7) or a reactive derivative thereof is usually from 0.1 to 10 equivalent(s) and, preferably, from 0.5 to 3 equivalent(s).
• the compound (IV-1) used means an amino compound corresponding to the aforementioned compound (II-1) and, to be more specific, an amino compound corresponding to the aforementioned (II-1-1) may be exemplified.
• the compound (IV-2) used means an amino compound corresponding to the aforementioned compound (II-2) and, to be more specific, an amino compound corresponding to the aforementioned (II-2-1) may be exemplified.
• the compound (IV-3) used means an amino compound corresponding to the aforementioned compound (II-3) and, to be more specific, an amino compound corresponding to the aforementioned (II-3-1) may be exemplified.
• the compound (IV-4) used means an amino compound corresponding to the aforementioned compound (II-4) and, to be more specific, an amino compound corresponding to the aforementioned (II-4-1) may be exemplified.
• the compound (IV-5) used means an amino compound corresponding to the aforementioned compound (II-5) and, to be more specific, an amino compound corresponding to the aforementioned (II-5-1) may be exemplified.
• the amount of the amide-forming reagent used varies depending upon the compound used, type of the solvent and other reaction conditions, it is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s) to one equivalent of the carboxylic acid compound (7) or a reactive derivative thereof.
• the amount of the condensing promoter used varies depending upon the compound used, type of the solvent and other reaction conditions, it is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s) to one equivalent of the carboxylic acid compound (7) or a reactive derivative thereof.
• Amount of the base used is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• an inert solvent is exemplified and, although there is no particular limitation therefor so far as it does not affect the reaction, its specific examples are methylene chloride, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, benzene, xylene, toluene, 1,4-dioxane, tetrahydrofuran, dimethoxyethane and mixed solvent thereof.
• examples of the preferred one are methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile and N,N-dimethylformamide, etc.
• Reaction temperature in this step is usually from -78°C to a boiling point of the solvent and, preferably, from 0°C to 30°C.
• Reaction time in this step is usually from 0.5 to 96 hour(s) and, preferably, from 3 hour to 24 hours.
• the amide-forming reagent and a condensing promoter used in this step one of them or two or more of them in a combination thereof may be able to be used.
• the compound (I-1) of the present invention prepared as such can be subjected to isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound (I-2) of the present invention is also able to be produced by the following method. [wherein, the symbols have the same meanings as above.]
• This step is a process for producing a compound (9) by the reaction of a compound (8) with 1,1-dimethyl-2-hydroxyethylamine in the presence of a base.
• Examples of the base used in this step are triethylamine, trimethylamine, N,N-diisopropylethylamine, N-methylmorpholine and pyridine, etc. and, among them, triethylamine, N,N-diisopropylamine and pyridine are preferred.
• Amount of the base used to one equivalent of the compound (8) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• Reaction temperature is usually from -78°C to 100°C and, preferably, from 0°C to 50°C.
• Reaction time is usually from 10 minutes to 48 hours and, preferably, from 30 minutes to 24 hours.
• reaction solvent there is no particular limitation for the reaction solvent so far as it does not affect the reaction and, to be more specific, its examples are chloroform, methylene chloride, 1,2-dichloroethane, THF, ethyl acetate, acetonitrile, 1,4-dioxane, toluene and dimethoxyethane, etc. where chloroform, methylene chloride and THF are preferred.
• the compound (9) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (10) by the reaction of the compound (9) produced in the above-mentioned step 8 with thionyl chloride.
• Amount of thionyl chloride used to one equivalent of the compound (9) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• Reaction temperature is usually from 0°C to 100°C and, preferably, from 0°C to 50°C.
• Reaction time is usually from 10 minutes to 48 hours and, preferably, from 10 minutes to 24 hours.
• reaction solvent used in this step anything may be used so far as it does not affect the reaction and its examples are benzene, methylene chloride and 1,2-dichloroethane, etc.
• the compound (10) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process to produce a compound (11) by the reaction of the compound (10) prepared in the above-mentioned step 9 with 1,4-cyclohexanedione-monoethylene ketal in the presence of a base.
• butyl lithium, lithium 2,2,6,6-tetramethylpiperidide, etc. may be exemplified and butyl lithium is preferred.
• Amount of the base used to one equivalent of the compound (10) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• Amount of 1,4-cyclohexanedione-monoethylene ketal used in this step to one equivalent of the compound (10) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• Reaction temperature is usually from -78°C to 100°C and, preferably, from -78°C to 50°C.
• Reaction time is usually from 10 minutes to 24 hours and, preferably, from 10 minutes to 12 hours.
• reaction solvent used in this step anything may be used so far as it does not affect the reaction and its examples are THF, diethyl ether and tert-butyl methyl ether, etc. where THF is preferred.
• the compound (11) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process to produce a compound (12) by the reaction of the compound (11) prepared in the above-mentioned step 10 with an acid.
• Amount of the acid used to one equivalent of the compound (11) is usually from 0.1 to 100 equivalent(s) and, preferably, from 0.1 to 10 equivalent(s).
• Reaction temperature is usually from 0°C to 200°C and, preferably, from 20°C to 100°C.
• Reaction time is usually from 1 hour to 72 hours and, preferably, from 1 hour to 48 hours.
• reaction solvent used in this step anything may be used so far as it does not affect the reaction and its examples are water, acetone, THF and 1,4-dioxane, etc. where acetone, THF, etc. are preferred.
• the compound (12) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (13) by subjecting the compound (12) produced in the above-mentioned step 11 to a reduction reaction.
• reaction in this step may be carried out by the same method as in the aforementioned step 3, by a method similar thereto or by a combination thereof with a conventional method.
• the compound (13) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (14) by the reaction of the compound (13) produced in the above-mentioned step 12 with a compound L 1 -Cl in the presence of a base.
• reaction in this step may be carried out by the same method as in the aforementioned step 4, by a method similar thereto or by a combination thereof with a conventional method.
• the compound (14) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (15) by the reaction of the compound (14) produced in the above-mentioned step 13 with a CN compound.
• reaction in this step may be carried out by the same method as in the aforementioned step 5, by a method similar thereto or by a combination thereof with a conventional method.
• the compound (15) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (16) by hydrolysis of the compound (15) produced in the above-mentioned step 14.
• reaction in this step may be carried out by the same method as in the aforementioned step 6, by a method similar thereto or by a combination thereof with a conventional method.
• the compound (16) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a process for producing a compound (I-2) of the present invention by the reaction of the compound (16) produced in the above-mentioned step 15 with a compound (IV-1), (IV-2), (IV-3), (IV-4) or (IV-5).
• reaction in this step may be carried out by the same method as in the aforementioned step 7, by a method similar thereto or by a combination thereof with a conventional method.
• Examples of the compound (IV-1) are N-methyl-N-(piperidinoethyl)amine, N-methyl-N-(pyrrolidinoethyl)amine, 1-(2-aminoethyl)piperidine, 1-(2-aminoethyl)pyrrolidine, N,N,N'-trimethylethylenediamine, N-cyclohexyl-N,N'-dimethylethylenediamine and N-ethyl-N-(piperidinoethyl)amine, etc.
• Examples of the compound (IV-2) are (S)-1-(2-pyrrolidinylmethyl)pyrrolidine, (S)-1-(2-pyrrolidinylmethyl)piperidine, (S)-1-(2-piperdinylmethyl)piperidine and (S)-1-(2-piperdinylmethyl)pyrrolidine, etc.
• Examples of the compound (IV-3) are 1-methylpiperazine, 1-isobutylpiperazine, 1-cyclopentylpiperazine, (R)-octahydropyrrolo[1,2-a]pyrazine and 1-ethyl-(3S)-methylpiperazine, etc.
• Examples of the compound (IV-4) are N-(1-cyclopentyl-3-pyrrolidinyl)-N-methylamine and N-(1-isobutyl-3-pyrrolidinyl)-N-methylamine, etc.
• Examples of the compound (IV-5) are 1-(1-isopropylpyrrolidin-2-yl)-N-methylmethaneamine, etc.
• the compound (1-2) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound of the present invention (I-3), (I-4) or (I-5) also can be produced by, for example, the following method. [wherein, R 61 represents a lower alkyl group, X represents a halogen atom and other symbols have the same meanings as above.]
• This step is a process for producing the compound (I-3), (I-4) or (I-5) of the present invention by the reaction of the compound represented by the formula (I-1-1), (I-1-2) or (I-1-3) which is the compound of the present invention covered by the aforementioned formula (I-1) with the compound (17) in the presence of a base.
• Examples of the base used are sodium hydride, potassium hydride, calcium hydride and butyl lithium, etc. Among them, NaH is preferred.
• Amount of the base used to one equivalent of the compound (I-1-1), (I-1-2) or (I-1-3) is usually form 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• the compound (17) used are ethyl iodide, methyl iodide, methyl trifluoromethylsulfonate, methyl methylsulfonate, methyl p-toluenesulfonate, methyl bromide and ethyl bromide, etc.
• Amount of the compound (17) used to one equivalent of the compound (I-1-1), (I-1-2) or (I-1-3) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• reaction solvent used in this step there is no particular limitation so far as it does not affect the reaction and its examples are N,N-dimethylformamide and THF, etc.
• Reaction temperature is usually from -78°C to 100°C and, preferably, from 0°C to 50°C.
• Reaction time is usually from 10 minutes to 48 hours and, preferably, from 10 minutes to 24 hours.
• the compound (I-3), (I-4) or (I-5) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound (I-6) of the present invention can be produced by, for example, the following method.
• Pro represents a protective group for amino group
• R 9 represents a hydrogen atom or a lower alkyl group
• R 10 represents a hydrogen atom, a lower alkyl group, an aryl group or a heteroaryl group or R 9 and R 10 together form a three- to nine-membered cycloalkyl group and other symbols have the same meanings as above.
• This step is a process to produce a compound (19) by the reaction of the above-mentioned compound (7) with the compound (18).
• Examples of an amide-forming reagent as such are thionyl chloride, oxalyl chloride, N,N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N,N'-carbonyldiimidazole, diphenylphosphoryl chloride, diphenylphosphoryl azide, N,N'-disuccinimidyl carbonate, N,N'-disuccinimidyl oxalate, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, ethyl chloroformate, isobutyl chloroformate, HATU and benzotriazo-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, etc.
• thionyl chloride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N-dicyclohexylcarbodiimide, HATU and benzotriazo-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, etc. are preferred.
• amide-forming reaction it is also possible to use a base and a condensing promoter together with the above-mentioned amide-forming reagent.
• Examples of the base used are a tertiary aliphatic amine such as trimethylamine, triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-azabicyclo[4.3.0]non-5-ene (DBN), etc.; an aromatic amine such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline and isoquinoline; etc.
• the tertiary aliphatic amine is preferred and, for example, triethylamine or N,N-diisopropylethylamine, etc. is particularly preferred.
• condensing promoter examples include N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-carboxyimide and 3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazole, etc. where N-hydroxybenzotriazole, etc. are preferred.
• Amount of the compound (18) used to one equivalent of the carboxylic acid derivative (7) or a reactive derivative thereof is usually from 0.1 to 10 equivalent(s) and, preferably, from 0.5 to 3 equivalent(s).
• Examples of the compound (18) used are 1-Boc-piperazine, 1-Boc-homopiperazine, 1-benzyloxycarbonylpiperazine, 1-acetylpiperazine, 1-benzoylpiperazine and 1-benzylpiperazine, etc.
• the amount of the amide-forming reagent used varies depending upon the compound used, type of the solvent and other reaction conditions, it is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s) to one equivalent of the carboxylic acid compound (7) or a reactive derivative thereof.
• the amount of the condensing promoter used varies depending upon the compound used, type of the solvent and other reaction conditions, it is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s) to one equivalent of the carboxylic acid compound (7) or a reactive derivative thereof.
• Amount of the base used is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• an inert solvent is exemplified and, although there is no particular limitation therefor so far as it does not affect the reaction, its specific examples are methylene chloride, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, ethyl acetate, methyl acetate, acetonitrile, benzene, xylene, toluene, 1,4-dioxane, tetrahydrofuran, dimethoxyethane and a mixed solvent thereof.
• examples of the preferred one are methylene chloride, chloroform, 1,2-dichloroethane, acetonitrile and N,N-dimethylformamie, etc.
• Reaction temperature in this step is usually from -78°C to a boiling point of the solvent and, preferably, from 0°C to 30°C.
• Reaction time in this step is usually from 0.5 to 96 hour(s) and, preferably, from 3 hour to 24 hours.
• the amide-forming reagent and a condensing promoter used in this step one or more thereof may be able to be combined and used.
• the compound (19) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a method to produce a compound (20) by removing the protective group for amino group of the compound (19) produced in the above-mentioned step 18.
• Removal of the protective group for amino group can be carried out by a method mentioned in a document (such as " Protective Groups in Organic Synthesis” by T. W. Green, second edition, John Wiley & Sons, 1991 ), by a method similar thereto or by combining those methods with a conventional method.
• the compound (20) prepared as such can be subjected to the next step with or without isolation and purification by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• This step is a method for producing a compound (I-6) of the present invention by the reaction of the compound (20) produced in the above-mentioned step 18 with the compound (21).
• the reaction in this step is the so-called reductive alkylation and the compound (I-6) of the present invention can be produced by the reaction of the compound (20) with the compound (21) in the presence of a base and a reducing agent.
• Examples of the compound (21) used are cyclobutanone, cyclopentanone, cyclohexanone, cycloheptanone, acetone, 3-pentanone, 2-butanone, 3-methyl-2-butanone, 3-hexanone, formaldehyde, acetaldehyde, propionaldehyde and isobutyraldehyde, etc.
• Amount of the compound (21) used to one equivalent of the compound (20) is usually from 1 to 10 equivalent(s) and, preferably, from 1 to 3 equivalent(s).
• Examples of the base used are triethylamine, trimethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine and N-methylpiperidine, etc.
• Amount of the base used to one equivalent of the compound (20) is usually from 0 to 5 equivalent(s) and, preferably, from 0 to 2 equivalent(s).
• Examples of the reducing agent used are ZnCl 2 -NaBH 3 CN, acetic acid-NaBH 3 CN, acetic acid-NaBH(OAc) 3 and sodium borohydride, etc. and, among them, ZnCl 2 -NaBH 3 CN, acetic acid-NaHB 3 CN, etc. are preferred.
• Amount of the reducing agent used to one equivalent of the compound (20) is usually from 1 to 20 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• reaction solvent used in this step there is no particular limitation for the reaction solvent used in this step so far as it does not affect the reaction and its examples are methanol, ethanol, chloroform, methylene chloride, THF and 1,4-dioxane where methanol, ethanol and methylene chloride are preferred.
• Reaction temperature is usually from 0°C to 100°C and, preferably, from 0°C to 50°C.
• Reaction time is usually from 10 minutes to 48 hours and, preferably, from 10 minutes to 24 hours.
• the compound (I-6) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound (I-2-1) of the present invention [wherein, any one or two of J, K and L is/are nitrogen atom(s) while other(s) is/are carbon atom(s), p is 1 or 2, wherein (I-2-1) may be substituted with a lower alkyl group, a lower alkoxy group, a halogen atom, a cyano group, etc.
• a pharmaceutically acceptable salt thereof can be produced by, for example, the following method [wherein, the symbols have the same meanings as above] using trans-5'- ⁇ [(trifluoromethyl)-sulfonyl]oxy ⁇ -3' -oxo-N-methyl-N-(2-pyrrolidin-1 -ylethyl)-spiro [cyclohexane-1, 1'-(3'H)-isobenzofuran]-4-carboxamide (hereinafter, it may be abbreviated as a compound (A)) which is a compound of Example 52 produced from trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro [cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (hereinafter, it may be abbreviated as a compound I-A) produced in Example 20 as a starting
• This step is a method for producing the compound (I-2-1) of the present invention by the reaction of the compound (A) or (B) with the compound (21) in the presence of a base and a palladium catalyst.
• Examples of the base used are sodium carbonate, cesium carbonate, cesium fluoride, calcium carbonate, sodium hydride, sodium carbonate, potassium carbonate, potassium phosphate, potassium acetate, potassium tert-butoxide and triethylamine, etc.
• Amount of the base to one equivalent of the compound (A) or (B) is usually from 0.1 to 20 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• Examples of the palladium catalyst used are tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, dichloro(1,1'-bis(diphenylphosphino)ferrocene) palladium and palladium acetate, etc.
• Amount of the palladium catalyst to one equivalent of the compound (A) or (B) is usually from 0.01 to 10 equivalent(s) and, preferably, from 0.05 to 5 equivalent(s).
• the compound (21) used are pyridin-3-ylboronic acid, pyridin-4-ylboronic acid, pyrimidin-5-ylboronic acid, 2-methoxypyrimidin-5-ylboronic acid, 2-methoxypyridin-5-ylboronic acid and 2-methylpyridin-5-ylboronic acid, etc.
• reaction solvent so far as it does not affect the reaction and examples thereof are ethylene glycol dimethyl ether, N,N-dimethylformamide, toluene, THF, 1,4-dioxane, benzene, acetone and methanol, etc.
• Reaction temperature is usually from 0°C to refluxing temperature of the reaction solvent and, preferably, from room temperature to 150°C.
• Reaction time is usually from 0.1 hour to 72 hours and, preferably, from 0.5 hour to 12 hours.
• the compound (I-2-1) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound represented by the formula (I-2-2) [wherein, one or two of J 1 to J 5 is/are nitrogen atom(s) while others are carbon atoms (with a proviso that at least one of J 1 and J 2 is a nitrogen atom), may be substituted by a lower alkyl group, a lower alkoxy group, halogen atom or cyano group and other symbols have the same meanings as above] of the present invention may, for example, be produced by the following method. [wherein, the symbols have the same meanings as above.]
• This step is a method for producing the compound (I-2-2) by the reaction of the above-mentioned compound (A) or (B) with the compound (22) in the presence of lithium chloride and a palladium catalyst.
• Amount of lithium chloride used to one equivalent of the compound (A) or (B) is usually from 0.01 to 10 equivalent(s) and, preferably, form 0.05 to 5 equivalent(s).
• Examples of the palladium catalyst used are tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, dichloro(1,1'-bis(diphenylphosphino)ferrocene) palladium and palladium acetate, etc.
• Amount of the palladium catalyst to one equivalent of the compound (A) or (B) is usually form 0.01 to 10 equivalent(s) and, preferably, from 0.05 to 5 equivalent(s).
• Examples of the compound (22) used are 2-(tri-n-butyl tin)pyrazine and 2-(tri-n-butyl tin)pyridine, etc.
• Amount of the compound (22) to one equivalent of the compound (A) or (B) is usually from 0.1 to 50 equivalent(s) and, preferably, from 1 to 10 equivalent(s).
• reaction solvent so far as it does not affect the reaction and examples thereof are N,N-dimethylformamide, toluene, THF, 1,4-dioxane, benzene and acetone, etc.
• Reaction temperature is usually from 0°C to refluxing temperature of the reaction solvent and, preferably, from room temperature to 150°C.
• Reaction time is usually from 0.1 hour to 72 hours and, preferably, from 0.5 hour to 12 hours.
• the compound (I-2-2) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound of the present invention represented by the formula (I-2-3) [wherein, alkyl represents a lower alkyl group having 1 to 6 carbon(s) and other symbols have the same meanings as above] can be produced by, for example, the following method. [wherein, alkyl represents a linear or branched alkyl group having 1 to 6 carbon(s) (the alkyl group may be substituted with one to three halogen atom(s) being same or different) and L 2 is a leaving group.]
• This step is a method for producing the compound (1-2-3) of the present invention by the reaction of the above-mentioned compound (I-A) or (I-B) with an alkyl halide (23) in the presence of a base.
• Examples of the base used are cesium carbonate, potassium carbonate, sodium carbonate and sodium hydride, etc.
• Amount of the base to one equivalent of the compound (I-A) or (I-B) is usually from 0.1 to 20 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• Examples of the compound (23) used are methyl iodide, ethyl iodide, propyl iodide, butyl iodide and 2-fluoro-1-(fluoromethyl)ethyl methanesulfonate, etc.
• Amount of the alkyl halide (23) to one equivalent of the compound (I-A) or (I-B) is usually from 0.1 to 50 equivalent(s) and, preferably, from 1 to 10 equivalent(s).
• reaction solvent there is no particular limitation for the reaction solvent so far as it does not affect the reaction and examples thereof are N,N-dimethylformamide, toluene, acetone, 1,4-dioxane and benzene, etc.
• Reaction temperature is usually from 0°C to refluxing temperature of the reaction solvent and, preferably, from room temperature to 150°C.
• Reaction time is usually from 0.1 hour to 72 hours and, preferably, from 0.5 hour to 12 hours.
• the compound (I-2-3) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound of the present invention represented by the formula (I-2-4) [wherein, one or two of J 11 to J 15 is/are nitrogen atom(s) while others are carbon atoms, may be substituted with a lower alkyl group, a lower alkoxy group, halogen atom or cyano group and other symbols have the same meanings as above] may be produced by, for example, the following method. [wherein, hal represents a halogen atom and other symbols have the same meanings as above.]
• This step is a method for producing the compound (1-2-4) of the present invention by the reaction of the above-mentioned compound (I-A) or (I-B) with a compound (25) in the presence of a base.
• Examples of the base used are cesium carbonate, potassium carbonate, sodium carbonate, potassium phosphate and sodium hydride, etc.
• Amount of the base to one equivalent of the compound (I-A) or (I-B) is usually from 0.1 to 20 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• Examples of the compound (24) used are 2-fluoropyridine, 2-chloropyrimidine, 2-chloropyrazine, 2-chloro-2-methoxypyrimidine, 5-bromopyrimidine-2-carbonitrile and 2-chloro-5-fluoropyrimidine etc.
• Amount of the compound (24) to one equivalent of the compound (I-A) or (I-B) is usually from 0.1 to 50 equivalent(s) and, preferably, from 1 to 10 equivalent(s).
• reaction solvent so far as it does not affect the reaction and examples thereof are N,N-dimethylformamide, N-methyl-2-pyrrolidone, toluene, acetone, benzene, 1,4-dioxane and THF, etc.
• Reaction temperature is usually from 0°C to refluxing temperature of the reaction solvent and, preferably, from room temperature to 150°C.
• Reaction time is usually from 0.1 hour to 72 hours and, preferably, from 0.5 hour to 12 hours.
• the compound (I-2-4) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound of the present invention represented by the formula (I-2-5) [wherein, J 21 represents a hydrogen atom, an alkanoyl group, a lower alkylsulfonyl group, diphenylmethyl group, formyl group or a lower alkoxycarbonyl group, represents a four- to six-membered nitrogen-containing alicyclic group and other symbols have the same meanings as above] can be produced by, for example, the following method. [wherein, Pro represents a protective group for amino group, L 3 represents a leaving group and other symbols have the same meanings as above.]
• This step is a method for producing the compound (1-2-A) of the present invention by the reaction of the above-mentioned compound (I-A) or (I-B) with a compound (25) in the presence of a base.
• Examples of the base used are potassium carbonate, cesium carbonate, sodium hydride, potassium phosphate and sodium carbonate, etc.
• Amount of the base to one equivalent of the compound (I-A) or (I-B) is usually from 0.1 to 20 equivalent(s) and, preferably, from 1 to 5 equivalent(s).
• Amount of the compound (25) used to one equivalent of the compound (I-A) or (I-B) is usually from 0.1 to 50 equivalent(s) and, preferably, from 1 to 10 equivalent(s).
• reaction solvent so far as it does not affect the reaction and examples thereof are N,N-dimethylformamide, N-methyl-2-pyrrolidone, toluene, acetone, benzene, 1,4-dioxane and THF, etc.
• Reaction temperature is usually from 0°C to refluxing temperature of the reaction solvent and, preferably, from room temperature to 150°C.
• Reaction time is usually from 0.1 hour to 72 hours and, preferably, from 0.5 hour to 12 hours.
• the compound (I-2-A) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• the compound (25) can be produced, for example, by the reaction of tert-butyl 4-hydroxypiperidine-1-carboxylate, tert-butyl 2-hydroxypyrrolidine-1-carboxylate, 1-(diphenylmethyl)azetidin-3-ol or the like with methanesulfonyl chloride in the presence of a base such as triethylamine.
• This step is a method to produce a compound (I-2-5-1) of the present invention where Pro 1 is hydrogen atom by removing the protective group for amino group of the compound (I-2-A).
• the reaction in this step can be carried out by a method mentioned in a document (such as " Protective Groups in Organic Synthesis” by T. W. Green, second edition, John Wiley & Sons, 1991 ), by a method similar thereto or by combining those methods with a conventional method.
• the compound (I-2-5-1) prepared as such can be isolated and purified by a known separation and purification means such as concentration, concentration in vacuo, crystallization, extraction with solvent, reprecipitation and chromatography.
• R 11 is introduced into NH of the compound (I-2-5-1) produced in the above-mentioned step 27 whereupon a compound (1-2-5-2) can be produced.
• R 11 are an alkanoyl group, a lower alkylsulfonyl group, diphenylmethyl group, formyl group or a lower alkoxycarbonyl group and more specific examples are acetyl group, propionyl group, methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, formyl group and methoxycarbonyl group, etc.
• R 11 With regard to a method for introducing R 11 into the compound (I-2-5-1), it may be carried out according to a method which has been commonly used in the field of organic chemistry such as that mentioned in a document (such as " Protective Groups in Organic Synthesis” by T. W. Green, second edition, John Wiley & Sons, 1991 ), by a method similar thereto or by combining those methods with a conventional method.
• the compound of the present invention represented by the formula (I-7), (I-8) or (I-9) [wherein, the symbols have the same meanings as above] can be produced by a method mentioned in a document (such as Journal of Organic Chemistry, 1976, volume 41, no. 15, pages 2628 to 2633 ), by a method similar thereto or by combining those methods with a conventional method.
• the compound of the present invention represented by the formula (I-10) [wherein, the symbols have the same meanings as above] can be produced by a method mentioned in a document (such as WO 95/28389 ), by a method similar thereto or by combining those methods with a conventional method.
• boron tribromide is used whereby methoxy group can be converted into hydroxyl group.
• Those compounds can be made into a pharmaceutically acceptable salt or ester by a conventional method and, reversely, conversion of salt or ester into a free compound also can be carried out by a conventional method.
• the carbamoyl-substituted spiro derivative according to the present invention can be present as a pharmaceutically acceptable salt and can be produced by a conventional method using the compound represented by the above-mentioned formula (I), (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9) or (I-10).
• Examples of the acid-addition salt are a salt with a hydrogen halide such as hydrochloride, hydrofluoride, hydrobromide and hydroiodide; with an inorganic acid salt such as nitrate, perchlorate, sulfate, phosphate and carbonate; with a lower alkyl sulfonate such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; with an arylsulfonate such as benzenesulfonate and p-toluenesulfonate; with an organic acid such as fumarate, succinate, citrate, tartrate, oxalate and maleate; and with an organic acid which is an amino acid such as glutamate and aspartate.
• a hydrogen halide such as hydrochloride, hydrofluoride, hydrobromide and hydroiodide
• an inorganic acid salt such as nitrate, perchlorate
• Examples of a base-addition salt are a salt with alkali metal such as sodium and potassium; a salt with alkali earth metal such as calcium and magnesium; an ammonium salt; and a salt with an organic base such as guanidine, triethylamine and dicyclohexylamine.
• the compound of the present invention may be also present as any hydrate or solvate of a free compound or a salt thereof.
• the compound represented by the formula (I) or (I-1), (I-2), (I-3), (I-4), (I-5), (I-6), (I-7), (I-8), (I-9) or (I-10) covered by the formula (I) may be administered either orally or parenterally.
• the compound of the present invention When the compound of the present invention is clinically used, it may be made into a pharmaceutical preparation by addition of a pharmaceutically acceptable additive thereto depending upon its dosage form.
• a pharmaceutically acceptable additive thereto depending upon its dosage form.
• various kinds of additives which have been commonly used in the field of pharmaceutical preparations may be used and examples thereof are gelatin, lactose, sucrose, titanium oxide, starch, crystalline cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white Vaseline, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysolvate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, acacia
• the dosage form prepared as a mixture of such an additive examples include a solid preparation such as tablets, capsules, granules, diluted powder and suppositories and a liquid preparations such as syrup, elixir and injection and they may be prepared by a common method in the field of pharmaceutical preparations.
• the liquid preparation it may be in a form which is dissolved or suspended in water or other appropriate medium in actual use. Particularly in the case of injection, it may be dissolved or suspended, if necessary, in a physiological saline solution or a glucose solution or buffer and preservative may be further added thereto.
• Such a preparation may contain the compound of the present invention in an amount of from 1.0 to 100% by weight and, preferably, from 1.0 to 60.0% by weight.
• the compound of the present invention may be made into a pharmaceutical preparation by, for example, the following Preparation Examples.
• Example 1 The compound of Example 1 which will be mentioned later (10 parts), 15 parts of heavy magnesium oxide and 75 parts of lactose are uniformly mixed to give diluted powder in a powdery or finely granular form of not larger than 350 ⁇ m. The diluted powder is placed in capsule containers to give a capsule preparation.
• Example 1 The compound of Example 1 which will be mentioned later (45 parts), 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water are uniformly mixed, disintegrated, granulated, dried and sieved to give a granular preparation where diameter is within 1,410 to 177 ⁇ m.
• a granular preparation is prepared by the same method as in Preparation Example 2 and 3 parts of calcium stearate is added to 96 parts of the granular preparation followed by subjecting to a compression molding to give tablets of 10 mm diameter.
• Those preparations may also contain other therapeutically effective medicament as will be mentioned below.
• the compound of the present invention can be used in combination with other medicament which is useful for the procedure (prevention or treatment) of metabolic disorder and eating disorder.
• Each component in such a combination can be administered in divided or single preparation(s) at different time or at the same time during the period for the procedure.
• the combination of the compound of the present invention with other medicament useful for the procedure of metabolic disorder or eating disorder principally includes a combination with any medicament which is useful for the procedure of metabolic disorder or eating disorder.
• the compound of the present invention also can be used in combination with a medicament (hereinafter, it will be referred to as "co-drug") which is effective for hypertension, obesity-related hypertension, hypertension-related diseases, cardiac hypertrophy, left ventricular hypertrophy, metabolic diseases, obesity, obesity-related diseases, etc.
• a medicament and the compound of the present invention may be administered simultaneously, separately or successively.
• the compound of the present invention is used together with one or more co-drug(s)
• it can be made into a pharmaceutical composition which is a single dosage form.
• a composition containing the compound of the present invention and the co-drug may be administered to the object to be administered simultaneously, separately or successively. In that case, the composition and the co-drug may be separately packed. They may be administered with a difference of time.
• Dose of the co-drug may be in accordance with the clinically used dose and may be appropriately selected depending upon the patient to be administered, administering route, disease, combination, etc. There is no particular limitation for the dosage form of the co-drug but the compound of the present invention and the co-drug may be just combined at the stage of administration.
• Examples of the dosage form as such are 1) administration of a single pharmaceutical preparation prepared by making the compound of the present invention and the co-drug into the preparation simultaneously, 2) a simultaneous administration, by the same administration route, of two kinds of pharmaceutical preparations where the compound of the present invention and the co-drug are made into preparations separately, 3) administration, by the same administration route with difference of time, of two kinds of pharmaceutical preparations where the compound of the present invention and the co-drug are made into preparations separately, 4) a simultaneous administration, by different administration routes, of two kinds of pharmaceutical preparations where the compound of the present invention and the co-drug are made into preparations separately and 5) administration, by different administration routes with difference of time, of two kinds of pharmaceutical preparations where the compound of the present invention and the co-drug are made into preparations separately.
• Compounding ratio of the compound of the present invention to the co-drug may be appropriately selected depending upon, for example, a patient to be administered, administering route and disease.
• Examples of the co-drug used in the present invention are remedy for diabetes, remedy for hyperlipemia, remedy for hypertension and remedy for obesity.
• the co-drug as such two or more kinds thereof may be used jointly.
• anti-obesity agent examples of the above-mentioned anti-obesity agent are as follows.
• the compound of the present invention can be combined with one or more of the above-mentioned co-drugs. Joint use of the compound of the present invention with one or more medicament(s) selected from the group consisting of remedy for diabetes and remedy for hyperlipemia is useful for prevention or treatment of metabolic diseases. Particularly when remedy for diabetes or remedy for hyperlipemia is further combined with the compound of the present invention in addition to remedy for hypertension and remedy for obesity, a preventive or treating effect for metabolic diseases is synergically achieved.
• the compound of the present invention When the compound of the present invention is used in a clinical field, its dose and administering frequency vary depending upon sex, age, body weight and degree of symptom of a patient, type and range of the aimed procedure effect, etc.
• 0.01 to 100 mg/kg or, preferably, 0.03 to 1 mg/kg per day for an adult is administered by dividing into one to several times a day.
• 0.001 to 10 mg/kg or, preferably, 0.001 to 0.1 mg/kg is administered by dividing into one to several times a day.
• silica gel 60 F 245 (Merck) was used as a plate and UV detector was used as a detecting means.
• silica gel for the column Wakogel TM C-300 (Wako Pure Chemical), KP-Sil (Biotage) or KP-NH (Biotage) was used; as to silica gel for a reverse-phase column, YMC-GEL TM ProC18 (Yamamura Kagaku Kenkyusho) was used; and, as to a reversed phase HPLC column, YMC-CombiPrep ProC18 (YMC) was used.
• Mass spectrum is measured by an electrospray ionization method (ESI) using Quattro II (manufactured by Micromass).
• NMR spectrum when measurement is carried out in a heavy dimethyl sulfoxide solution, dimethyl sulfoxide is used as an internal standard, measurement is conducted using a spectrophotometer of a type of Gemini-200 (200 MHz; Varian), Gemini-300 (300 MHz; Varian), Mercury 400 (400 MHz; Varian) or Inova 400 (400 MHz; Varian) and the all ⁇ values are shown in ppm.
• the compounds of Examples 2 to 22 can be produced using the corresponding carboxylic acid and amine as materials by the same method as in Example 1, by a method similar thereto or by combining such methods with a conventional method.
• the title compound was prepared by the method according to Example 1 using trans-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-2 and N-methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-2 and N-methyl-N-(pyrrolidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-2 and 1-(2-aminoethyl)piperidine as materials.
• the title compound was prepared by the method according to Example 1 using trans-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-2 and 1-(2-aminoethyl)pyrrolidine as materials.
• the title compound was prepared by the method according to Example 1 using trans-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-2 and 1-ethyl-(3S)-methylpiperazine as materials.
• the title compound was prepared by the method according to Example 1 using trans-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-2 and (R)-octahydropyrrolo[1,2-a]pyrazine as materials.
• the title compound was prepared by the method according to Example 1 using trans-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-2 and N-(1-cyclopentyl-3-pyrrolidinyl)-N-methylamine as materials.
• the title compound was prepared by the method according to Example 1 using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and N-methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-5-fluoro-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-4 and N-methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-5-fluoro-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-4 and (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine as materials.
• the title compound was prepared by the method according to Example 1 using trans-7-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 2-1 and N-methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-7-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 2-1 and N-methyl-N-(piperazinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-6-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 2-2 and N-methyl-N-(piperazinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-1'-(methylsulfonyl)-1',2'-dihydrospiro[cyclohexane-1,3'-indole]-4-carboxylic acid and N-methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-2'-methyl-3'-oxo-2',3'-dihydro-spiro[cyclohexane-1,1'-isoindole]-4-carboxylic acid produced in Reference Example 4 and N-methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using cis-2'-methyl-3'-oxo-2',3'-dihydrospiro[cyclohexane-1,1'-isoindole]-4-carboxylic acid produced in Reference Example 4 and N-methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and N-methyl-N-(pyrrolidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-5-fluoro-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-4 and N-methyl-N-(pyrrolidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using trans-5-hydroxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 3 and N-methyl-N-(pyrrolidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 1 using 3H-spiro[2-benzofuran-1,4'-piperidine]-3-one hydrochloride monohydrate and 4-piperidine-1-butanoic acid as materials.
• the title compound was prepared by the method according to Example 1 using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-methyl-4'-carboxylic acid produced in Reference Example 5 and N-methyl-N-(pyrrolidinoethyl)amine as materials.
• Triethylamine (0.368 mL), tert-butyl 1-piperazine-carboxylate (416 mg) and 2N solution of 2-chloro-1,3-dimethylimidazolinium chloride in dichloromethane (1.10 mL) were added at 0°C to a solution of trans-3-oxo-3H-spiro-[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid (500 mg) produced in Reference Example 1-2 in chloroform (10 mL) and, after that, the mixture was stirred at 0°C for 30 minutes. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate and the mixture was extracted with ethyl acetate.
• the compounds of Examples 26 to 31 can be produced by the same method as in Example 25, by a method similar thereto or by a combination of those methods with a conventional method by using the corresponding ketone or aldehyde as materials.
• Example 25 A method according to Example 25 was carried out to produce the title compound using trans-piperazinyl-3'-oxo-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide hydrochloride produced in Example 25 and cyclopentanone as materials.
• Example 17 A method according to Example 17 was carried out to produce the title compound using trans-piperaziny1-3'-oxo-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide hydrochloride produced in Example 25 and cyclobutanone as materials.
• Example 25 A method according to Example 25 was carried out to produce the title compound using trans-piperazinyl-3'-oxo-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide hydrochloride produced in Example 25 and 3-pentanone as materials.
• Example 25 A method according to Example 25 was carried out to produce the title compound using trans-piperazinyl-3'-oxo-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide hydrochloride produced in Example 25 and 2-butanone as materials.
• Example 17 A method according to Example 17 was carried out to produce the title compound using trans-piperazinyl-3'-oxo-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide hydrochloride produced in Example 25 and acetone as materials.
• Example 25 A method according to Example 25 was carried out to produce the title compound using trans-piperazinyl-3'-oxo-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide hydrochloride produced in Example 25 and propionaldehyde as materials.
• Fluoromethyl tosylate (0.05 mL) and potassium carbonate (50 mg) were added to a solution of trans-5'-hydroxy-3'-oxo-(N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (50 mg) produced in Example 23 in acetone (0.8 mL) and the mixture was stirred in a sealed tube at 70°C for 20 hours. After water was added thereto, the mixture was extracted with ethyl acetate.
• Triethylamine (0.811 mL) was added to a solution of 3H-spiro[2-benzofuran-1,4'-piperazine]-3-one hydrochloride monohydrate (300 mg) in chloroform (5.0 mL), then triphosgene (345 mg) was added thereto at 0°C and the mixture was stirred at 0°C for 20 minutes.
• triphosgene 345 mg was added thereto at 0°C and the mixture was stirred at 0°C for 20 minutes.
• To the reaction solution was added a saturated aqueous solution of sodium bicarbonate followed by extracting with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo.
• the compounds of Examples 34 to 42 can be produced using the corresponding amine as a material by the same method as in Example 33, by a method similar thereto or by combining such methods with a conventional method.
• the title compound was prepared by the method according to Example 33 using 3H-spiro[2-benzofuran-1,4'-piperidine]-3-one hydrochloride and methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 33 using 4-fluoro-3H-spiro[2-benzofuran-1,4'-piperidine]-3-one hydrochloride and methyl-N-(piperidino-ethyl)amine as materials.
• the title compound was prepared by the method according to Example 33 using 2-methyl-spiro[isoindole-1,4'-piperidine]-3(2H)-one hydrochloride and methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 33 using 2-(ethylsulfonyl)-1,2-dihydrospiro-[indole-3,4'-piperidine] and methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 33 using 3-(methylsulfonyl)-2,3-dihydrospiro[indene-1,4'-piperidine] and methyl-N-(piperidinoethyl)-amine as materials.
• the title compound was prepared by the method according to Example 33 using 5-fluoro-3H-spiro[2-benzofuran-1,4'-piperidine] and methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 33 using 3,3-dimethyl-3H-spiro[2-benzofuran-1,4'-piperidine] and methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 33 using spiro[isoindole-1,4'-piperidine]-3(2H)-one and methyl-N-(piperidinoethyl)amine as materials.
• the title compound was prepared by the method according to Example 33 using spiro[indene-1,4'-piperidine]-3(2H)-one and methyl-N-(piperidinoethyl)amine as materials.
• N,N-Diisopropylethylamine (2.27 mL), trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid (3.00 g) produced in Reference Example 1-3 and HATU (4.96 g) were added to a solution of N-methylethanolamine (816 mg) in chloroform (20 mL) at 0°C and then stirred for 15 hours at room temperature in a nitrogen atmosphere. To the reaction solution was added a saturated aqueous solution of ammonium chloride followed by extracting with ethyl acetate.
• the compounds of Examples 44 to 49 can be produced using the corresponding amine as a material by the same method as in Example 43, by a method similar thereto or by combining such methods with a conventional method.
• Example 43 A method according to Example 43 was carried out to produce the title compound using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and diethylamine as materials.
• Example 43 A method according to Example 43 was carried out to produce the title compound using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and azetidine as materials.
• Example 43 A method according to Example 43 was carried out to produce the title compound using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and (2R)-2-methylpyrrolidine hydrobromide as materials.
• Example 43 A method according to Example 43 was carried out to produce the title compound using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and 2-methylpiperidine as materials.
• Example 43 A method according to Example 43 was carried out to produce the title compound using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and azepane as materials.
• Example 43 A method according to Example 43 was carried out to produce the title compound using trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylic acid produced in Reference Example 1-3 and azocane as materials.
• reaction solution was diluted with ethyl acetate and washed with a saturated aqueous solution of sodium bicarbonate and a saturated saline solution.
• organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
• Tetrakistriphenylphosphine palladium (66.9 mg), pyridin-3-ylboronic acid (47.4 mg), sodium carbonate (123 mg) and water (2.0 mL) were successively added at room temperature to a solution of trans-5' - ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ - -3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro [cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (100 m g) prepared in Example 51 in ethylene glycol dimethyl ether (3 mL) and stirred at 80°C for 1 hours.
• reaction solution was diluted with ethyl acetate and washed with a saturated saline solution.
• the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
• the compounds of Examples 54 to 56 can be produced using the corresponding boronic acid as a material by the same method as in Example 53, by a method similar thereto or by combining such methods with a conventional method.
• Example 53 A method according to Example 53 was carried out to produce the title compound using trans- ⁇ (trifluoromethyl)sulfonyl ⁇ -oxy ⁇ -3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'(3H)-isobenzofuran]-4-carboxamide produced in Example 51 and pyridin-4-ylboronic acid as materials.
• Example 53 A method according to Example 53 was carried out to produce the title compound using trans- ⁇ [(trifluoromethyl)sulfonyl]-oxy ⁇ -3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'(3H)-isobenzofuran]-4-carboxamide produced in Example 51 and pyrimidin-5-ylboronic acid as materials.
• Example 53 A method according to Example 53 was carried out to produce the title compound using trans-5'- ⁇ [(trifluoromethyl)sulfonyl]-oxy ⁇ -3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclo-hexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 52 and 2-methoxypyrimidin-5-ylboronic acid as materials.
• Tetrakistriphenylphosphine palladium (44.6 mg), 2-(tri-n-butyl tin)pyrazine (85.4 mg) and lithium chloride (24.5 mg) were successively added at room temperature to a solution of trans-5'- ⁇ [(trifluoromethyl)sulfonyl]oxy ⁇ -3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (100 mg) produced in Example 51 in N,N-dimethylformamide (3.0 mL) and stirred at 100°C throughout the night.
• the reaction solution was diluted with ethyl acetate and washed with a saturated saline solution.
• the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
• the compounds of Examples 58 to 60 can be produced using the corresponding tin reagent as a material by the same method as in Example 57, by a method similar thereto or by combining such methods with a conventional method.
• Example 57 A method according to Example 57 was carried out to produce the title compound using trans-5'- ⁇ (trifluoromethyl)-sulfonyl ⁇ oxy ⁇ -3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 51 and 2-(tri-n-butyl tin)pyridine as materials.
• Example 57 A method according to Example 57 was carried out to produce the title compound using trans-5'- ⁇ (trifluoromethyl)-sulfonyl ⁇ -oxy ⁇ -3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'(3H)-isobenzofuran]-4-carboxamide produced in Example 52 and 2-(tri-n-butyl tin)pyridine as materials.
• Example 57 A method according to Example 57 was carried out to produce the title compound using trans-5'- ⁇ [(trifluoromethyl)sulfonyl ⁇ oxy ⁇ -3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 52 and 2-(tri-n-butyl tin)pyridine as materials.
• reaction solution was diluted with ethyl acetate and washed with a saturated saline solution.
• the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
• reaction solution was diluted with ethyl acetate and washed with a saturated saline solution.
• the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo.
• Example 64 A method according to Example 64 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 20 and 2-iodopropane as materials.
• 1,3-Difluoropropan-2-ol (0.075 mL) was dissolved in ethyl acetate (2 mL) and then triethylamine (0.12 mL) and methanesulfonyl chloride (0.062 mL) were successively added at room temperature thereto. After the mixture was stirred at room temperature for 10 minutes and the solid separated out therefrom was filtered.
• Example 66 A method according to Example 66 was carried out to produce the title compound using trans- 5 '-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'(3H)-iso-benzofuran]-4-carboxamide produced in Example 20 and 1,3-difluoropropan-2-ol as materials.
• Example 68 A method according to Example 68 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3H)-iso-benzofuran]-4-carboxamide produced in Example 23 and 2-chloropyrimidine as materials.
• Example 68 A method according to Example 68 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3H)-iso-benzofuran]-4-carboxamide produced in Example 23 and 2-chloropyrazine as materials.
• Example 68 A method according to Example 68 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro [cyclohexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 20 and 2-chloropyrimidine as materials.
• Example 68 A method according to Example 68 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 20 and 2-chloro-2-methoxypyrimidine as materials.
• Example 68 A method according to Example 68 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'(3H)-iso-benzofuran]-4-carboxamide produced in Example 20 and 2-chloropyrazine as materials.
• Example 68 A method according to Example 68 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'(3H)-iso-benzofuran]-4-carboxamide produced in Example 20 and 5-bromopyrimidine-2-carbonitrile as materials.
• Example 68 A method according to Example 68 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 20 and 2-chloro-5-fluoropyrimidine as materials.
• Triethylamine (0.29 mL) and methanesulfonyl chloride (0.20 mL) were successively added at room temperature to a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (391 mg) in ethyl acetate (5 mL). After the mixture was stirred at room temperature for 15 minutes, the solid separated out therefrom was filtered.
• the resulting compound (512 mg) was dissolved in a 4N hydrogen chloride solution in ethyl acetate (10 mL) and the reaction solution was stirred at room temperature for 1 hour.
• the reaction solution was concentrated in vacuo to give a dihydrochloride (490 mg, 70%) of the title compound.
• a method according to Examples 76 and 77 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro [cyclohexane-1,1'-(3H)-isobenzofuran]-4-carboxamide produced in Example 23 and tert-butyl 2-hydroxypyrrolidine-1-carboxylate as materials.
• a method according to Examples 76 and 77 was carried out to produce the title compound using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro [cyclohexane-1,1'(3H)-isobenzofuran]-4-carboxamide produced in Example 20 and tert-butyl 4-hydroxypiperidine-1-carboxylate as materials.
• a method according to Examples 76 and 77 was carried out to produce the title compound using trans-5' -hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'(3H)-isobenzofuran]-4-carboxamide produced in Example 20 and tert-butyl 2-hydroxypyrrolidine-1-carboxylate as materials.
• a 20% by weight palladium hydroxide catalyst (200 mg) was added to a solution of trans-5'-4- ⁇ [1-(diphenylmethyl)-azetidin-3-yl]oxy ⁇ -3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (501 mg) produced in Example 81 in ethanol (5.0 mL) and stirred in a 60 psi hydrogen atmosphere at room temperature throughout the night.
• Example 77 A method according to Example 77 was carried out using trans-5'-(Azetidin-3-yloxy)-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide produced in Example 82 as materials to produce the title compound.
• Triethylamine (0.027 mL) and methanesulfonyl chloride (0.012 mL) were successively added to a solution of trans-5'-(piperidin-4-yloxy)-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide dihydrochloride (59.7 mg) produced in Example 76 in ethyl acetate (3.0 mL) and stirred at room temperature throughout the night. After the reaction solution was diluted with ethyl acetate, it was washed with a saturated saline solution.
• a method according to Examples 76 and 84 was carried out using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide produced in Example 23 and tert-butyl 2-hydroxypyrrolidine-1-carboxylate as materials to produce the title compound.
• a method according to Examples 76 and 84 was carried out using trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-pyrrolidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide produced in Example 20 and tert-butyl 2-hydroxypyrrolidine-1-carboxylate as materials to produce the title compound.
• Example 84 A method according to Example 84 was carried out using trans-5'-(azetidin-3-yloxy)-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide produced in Example 82 as a material to produce the title compound.
• Methyl chloroformate (0.013 mL) and N,N-diisopropylethylamine (0.037 mL) were successively added to a solution oftrans-5'-(azetidin-3-yloxy)-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (46.5 mg) produced in Example 82 in tetrahydrofuran (1.0 mL) followed by stirring at room temperature for 1 hour.
• Propionyl chloride (0.018 mL) and N,N-diisopropylethylamine (0.055 mL) were successively added to a solution of trans-5'-(azetidin-3-yloxy)-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (68.5 mg) produced in Example 82 in tetrahydrofuran (1.0 mL) followed by stirring at room temperature for 1 hour.
• a 30% aqueous solution of sulfuric acid (5.0 mL) was added to a solution of 5-(2-fluoroethoxy)-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carbonitrile (700 mg) produced in the above (4) in 1,4-dioxane (5.0 mL) and, after that, the mixture was stirred at 100°C for 2 days.
• To the reaction solution was added a 4N aqueous solution of sodium hydroxide at 0°C to adjust to pH ca. 3 followed by extracting with ethyl acetate.
• the title compound was produced by the same method as Reference Example 1-1, by a method similar thereto or by a combination thereof with a common method using 2-bromobenzoic acid as a material.
• the title compound was produced by the same method as Reference Example 1-1, by a method similar thereto or by a combination thereof with a common method using 2-bromo-5-methoxybenzoic acid as a material.
• the title compound was produced by the same method as Reference Example 1-1, by a method similar thereto or by a combination thereof with a common method using 2-bromo-5-fluorobenzoic acid as a material.
• Triethylamine (23.0 mL) was added to a solution of 2-amino-2-methyl-1-propanol (14.4 g) in THF (200 mL), 3-methoxybenzoyl chloride (25.0 g) was dropped thereinto at 0°C and the mixture was stirred at room temperature for 1 day. After water was added to the reaction solution, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. Thionyl chloride (25 mL) was dropped into the resulting residue at 0°C and stirred at room temperature for 3 hours.
• a 40% methanolic solution (20.0 mL) of methylamine was added to a solution of ethyl 4-oxocyclohexanecarboxylate (10.0 g) in diethyl ether (100 mL) and stirred at room temperature for 5.5 hours. Drylite (10.0 g) was added thereto followed by stirring at room temperature for 18 hours. After it was filtered, the filtrate was concentrated. The resulting residue was dissolved in toluene (100 mL), then triethylamine (8.20 mL) and 2-iodobenzoyl chloride (10.97 g) were added thereto and the mixture was stirred for 2 days at 80°C in a nitrogen atmosphere.
• the resulting trans-cis mixture in about 3:1 (831 mg) was dissolved in methanol (15 mL), a 2N aqueous solution of sodium hydroxide (4.34 mL) was added thereto and the mixture was stirred at room temperature for one day.
• n-Butyl lithium (1.6M solution in hexane) (1.40 mL) was added, at -78°C, to a solution of diisopropylamine (0.31 mL) in tetrahydrofuran (10 mL) and the mixture was stirred at -78°C for 30 minutes.
• a solution of methyl trans-5-methoxy-3-oxo-3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-carboxylate 500 mg
• tetrahydrofuran (10 mL) followed by stirring at -78°C for 1 hour.
• a cDNA sequence coding for human histamine H3 receptor [refer to WO 00/39164 ] was cloned to an expression vector pCR2.1, pEF1x (manufactured by Invitrogen) and pCI-neo (manufactured by Promega).
• the resulting expression vector was transfected to host cells HEK293 and CHO-K1 (American Type Culture Collection) by a cationic lipid method [refer to Proceedings of the National Academy of Sciences, the United States of America, volume 84, page 7413 (1987 )] to give histamine H3 receptor-expressed cells.
• a membrane specimen prepared from the cells where histamine H3 receptor was expressed was incubated at 25°C for 2 hours in an assay buffer (50 mM Tris buffer, pH 7.4) together with a test compound (the compound of Example 1) and 20,000 cpm of [3H]N- ⁇ -methylhistamine (manufactured by NEN) and then filtered using a glass filter GF/C. After washing with a 50 mM Tris buffer of pH 7.4, radiation activity on the glass filter was determined.
• an assay buffer 50 mM Tris buffer, pH 7.4
• test compound the compound of Example 1
• 20,000 cpm of [3H]N- ⁇ -methylhistamine manufactured by NEN
• Non-specific bond was measured in the presence of a 10 ⁇ M thioperamide (manufactured by Sigam) to determine a 50% inhibition concentration (IC 50 value) of the test compound to a specific N-alpha-methylhistamine bond [refer to Molecular Pharmacology, volume 55, page 1101 (1999 )].
• IC 50 value 50% inhibition concentration of the test compound to a specific N-alpha-methylhistamine bond
• the IC 50 value of the compound of Example 10 was 4 nM
• that of the compound of Example 14 was 9 nM
• that of the compound of Example 58 was 0.08 nM
• that of the compound of Example 68 was 0.67 nM.
• a novel substance having an antagonistic action against a histamine H3 receptor (an action which inhibits the bonding of histamine to histamine H3 receptor) or an inverse agonistic action against the same (an action which suppresses a homeostatic activity of histamine H3 receptor) or, in other words, a novel substance acting as a histamine H3 receptor agonist or antagonist in living body.
• the carbamoyl-substituted spiro derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention has a strong histamine H3 receptor antagonistic action or inverse agonistic action and is useful for prevention or treatment of metabolic diseases such as obesity, diabetes, dysendocrinism, hyperlipemia, gout and fatty liver; circulatory disease such as stenocardia, acute congestive cardiac insufficiency, myocardial infarction, coronary sclerosis, hypertension, renal disease and electrolyte imbalance; or central and peripheral neural diseases such as sleep disorder, disease accompanied by sleep disorder (e.g., idiopathic hypersomnia, repetitive hypersomnia, true hypersomnia, narcolepsy, sleep periodic limb movement disorder, sleep apnea syndrome, circadian rhythm disorder, chronic fatigue syndrome, REM sleep disorder, senile insomnia, sleep unwholesomeness of night-work laborers, idiopathic insomnia, repetitive insomnia, true insomnia, depression, anxiety

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